Stable solutions of pge-type compounds

ABSTRACT

Stable solutions of PGE-type compounds are obtained by dissolving the compounds in an anhydrous, water-miscible, pharmacologically acceptable, dipolar aprotic solvent.

United States. Patent [191 Stehle et al'.

[451 Aug. 13, 1974 STABLE SOLUTIONS OF PGE-TYPE COMPOUNDS [75]Inventors: Randall G. Stehle; Thomas O.

Oesterling, both of Kalamazoo,

Mich.

[731 Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: May 11, 1973 [21] Appl. No.: 359,486

Related U.S. Application Data [63] Continuation-in-part of Ser. No.194,686, Nov. 1,

1971, abandoned.

[52] U.S. Cl 424/312, 424/318, 260/468 D, 260/514 Brummer J. Pharmacy &Pharmacology, Vol. 23, (1971), Pages 804 & 805.

Primary ExaminerSam Rosen 7] ABSTRACT Stable solutions of POE-typecompounds are obtained by dissolving the compounds in an anhydrous,watermiscible, pharmacologically acceptable, dipolar aprotic solvent.

16 Claims, No Drawings 1 STABLE SOLUTIONS OF POE-TYPE COMPOUNDS CROSSREFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of our copending application Ser. No. 194,686,filed Nov. 1, 1971, now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to novelcompositions of matter and to methods for using same. More specifically,

this invention is concerned with novel solutions of prostaglandin-likecompounds of the PGE-type in an anhydrous, water-miscible,pharmacologically acceptable, dipolar aprotic solvent in a concentrationof at least one mg. per ml. This invention also relates to a process fordispensing prostaglandin-like compounds of the PGE-type which comprisesdissolving the compound in an anhydrous, water-miscible,pharmacologically acceptable, dipolar aprotic solvent in a concentrationof at least one mg. per ml.; packaging the resulting solution in unitdose containers; diluting the contents of a container into a liquid orsolid vehicle; and administering said vehicle to administer atherapeutic dose. This invention also relates to a process fordispensing prostaglandin-like compounds of the PGE-type which comprisesdissolving said compound in an anhydrous, water-miscible,pharmacologically-acceptable, dipolar aprotic solvent in a concentrationof at least 1 mg. per

ml. sterilizing the resulting solution; aseptically packag-Prostaglandins of the E-type (POE-type) all have the followingstructural feature:

The prostaglandin known as prostaglandin E (PS5,) has the formula:

1 coon HO 05 III The prostaglandin known as prostaglandinE (PGE has theformula:

.7 7... The prostaglandin known as prostaglandin E (PGE has the formula:

COOH

Esters of prostaglandins of the E-type are also known in the art. See,for example, US. Pat. Nos. 3,069,322 andNo. 3,598,858.

As is known in the art, prostaglandins of the E-type and their estersare extremely potent in causing various biological responses. For thatreason, these compounds are useful for pharmacological andpharmaceutical purposes. See, for example, Bergstrom et al., Pharmacol.Rev. 20, l (1968), and references cited therein. A few of thosebiological responses are systemic blood pressure lowering as measured,-for example, in anesthetized (pentobarbital sodium) pentolinium-treatedrats with indwelling aortic and right heart cannulas; stimulation ofsmooth muscle as shown, for example, by tests on strips of guinea pigileum, rabbit duodenum, or gerbil colon; potentiation of other smoothmuscle stimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion as shown in dogs with secretionstimulated by food or histamine infusion; activity on the centralnervous system; controlling spasm and facilitating breathing inasthmatic conditions; and decreasing blood platelet adhesiveness asshown by platelet-to-glass adhesivenes's, and inhibition of bloodplatelet aggregation and thrombus formation induced by various physicalstimuli, e.g., arterial injury, and various biochemical stimuli,-e.g.,ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these known prostaglandins of theE-type and their esters are useful to study, prevent, contrOl, oralleviate a wide variety of diseases and undesirable physiologicalconditions in birds and mammals, including humans, useful domesticanimals, pets, and zoological specimens, and in laboratory animals, forexample, mice, rats, rabbits, and monkeys.

For example, these E-type prostaglandins are useful in mammals,including man, as'nasal decongestants.

For this purpose, the compounds are used in a dose range of about 10 pg.to about 10 mg. per ml. of a pharmacologically suitable liquid vehicleor as an aerosol spray, both for topical application.

The E-type prostaglandins are useful in the treatment of asthma. Forexample, these compounds are useful as bronchodilators or as inhibitorsof mediators, such as SRS-A, and histamine which are released from cellsactivated by an antigen-antibody complex. Thus, "these compounds controlspasm and facilitate breathing in conditions such as bronchial. asthma,bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes,these compounds are administered in a variety of dosage forms, e.g.,orally in the form of tablets, capsules, or liquids; rectally in theform of suppositories; parenterally, subcutaneously, or intramuscularly,with intravenous administration being preferred in emergency situations;by inhalation in the form of aerosols or solutions for nebulizers; or byinsufflation in the form of powder. Doses in the range of about 0.01 to5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dosedepending on the age, weight, and condition of the patient and on thefrequency and route of administration. For the above use theseprostaglandins can be combined advantageously with other antiasthmaticagents, such as sympathomimetics (isoproterenol, phenylephrine,ephedrine, etc.); xanthinederivatives (theophylline and aminophylline);and corticosteroids (ACTH and predinisolone). Regarding use of thesecompounds see South African Pat. No. 681 ,055.

The E-type prostaglandins are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 g. to about 500 pg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about mg. per kg. of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

The E-type prostaglandins are useful whenever it is desired to inhibitplatelet aggregation, to reduce the adhesive character of platelets, andto remove or prevent the formation of thrombi in mammals, including man,rabbits,and rats. For example, these compounds are useful in thetreatment and prevention of myocardial infarcts, to treat and preventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. For these purposes, these compoundsare administered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in theform of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the rangeabout 0.005 to about 20 mg. per kg. of body weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

The E-type prostaglandins are especially useful as additives to blood,blood products, blood substitutes, and other fluids which areused inartificial extracorporeal circulation and perfusion of isolated bodyportions,

e.g., limbs and organs, whether attached to the original body, detachedand being preserved or prepared for transplant, or attached to a newbody. During these circulations and perfusions, aggregated plateletstend to block the blood vessels and portions of the circulationapparatusThis blocking is avoided by the presence of these compounds.For this purpose, the compound is added gradually or in single ormultiple portions to the circulating blood, to the blood of the donoranimal, to the perfused body portion, attached or detached, to therecipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

The E-type prostaglandins are extremely potent in causing stimulation ofsmooth muscle, and are also highly active in potentiating other knownsmooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin,and the various ergot alkaloids including derivatives and analogsthereof. Therefore, PGE for example, is useful in place of or incombination with less than usual amounts of these known smooth musclestimulators, for example, to.relieve the symptoms of paralytic ileus, orto control or prevent atonic uterine bleedingafter abortion or delivery,to aid in expulsion of the placenta, and during the puerperium. For thelatter purpose, the E-type prostaglandin is administered by intravenousinfusion immediately after abortion or delivery at a dose in the rangeabout 0.01 to about pg. per kg. of body weight per minute until thedesired effect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The E-type prostaglandins are useful as hypotensive agents to reduceblood pressure in mammals, including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 to about 50 pg. per kg; of body weight per minute or in single ormultiple doses of about 25 to 500 pg. per kg. of body weight total perday.

The E-type prostaglandins are useful in place of oxytocin to inducelabor in pregnant female animals, in-

cluding man, cows, sheep, and pigs, at or near term, or in pregnantanimals with intrauterine death of the fetus from about 20 weeks toterm. For this purpose, the compound is infused intravenously at a doseof 0.01 to 50 pg. per kg. of body weight per minute until or near thetermination of the second stage of labor, i.e., expulsion of the fetus.These compounds are especially useful when the female is one or moreweeks post-mature and natural labor has not started, or 12 to 60 hoursafter the membranes have ruptured and natural labor has not yet started.An alternative route of administration is oral.

The E-type prostaglandins are useful for controlling the reproductivecycle in ovulating female mammals, including humans and animals such asmonkeys, rats,

rabbits, dogs, cattle, and the like. By the term ovulating femalemammals is meant animals which are mature enough to ovulate but not soold that regular ovulation has ceased. For that purpose, PGE forexample, is administered systemically at a dose level in the range 0.001mg. to about 2 mg. per kg. of body weight of the female mammal,advantageously during a span of time starting approximately at the timeof ovulation and ending approximately at the time of menses or justprior to menses. lntravaginal and intrauterine are alternative routes ofadministration. Additionally, expulsion of an embryo or a fetus isaccomplished by similar administration of the compound during the firstthird of the normal mammalian gestation period.

The E-type prostaglandins are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstretrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the PGE-type compounds areadministered locally or systemically. PGE for example, is administeredorally or .vaginally at doses of about 5 to 50 mg. per treatment of anadult female human, with from one to five treatments per 24 hour period.PGE is also administered intramuscularly or subcutaneously at doses ofabout one to 25 mg. per treatment. The exact dosages for these purposesdepend on the age, weight, and condition of the patient or animal.

Many prostaglandin-like compounds of the POE-type are also known in theart. All of these have the same cyclopentane ring structural feature offormula 11, above, but differ from the prostaglandins of the E-type inone or more other structural aspects, for example, in having one or moresubstituents, for example, alkyl, fluoro, phenyl, or cycloalkyl, oneither or both side chains, in having fewer or more methylene groups inone or both of the side chains, in having a hetero atom, for example,oxygen in place of a side-chain methylene group, in having cis ratherthan a trans or a trans rather than a cis configuration for a side-chaincarbon-carbon double bond, or in any combination of those structuralaspects. With reference to the numbering system of prostanoic acid(formula I above), some examples of E-type prostaglandin-like compoundsare IS-methyI-PGE B-15-methyl-PGE,, 15-methyl-PGE 155-15- methyl-PGE16,16-dimethyl-PGE 16,16-dimethyl- PGE 3-oxa-PGE 3-oxa-PGE 7-oxa-PGE,,17- phenyl-l8,l9,20 -trinor-PGE PGE lS-methyl ether,

6 PGE; 15-methyl ether, 5,6-trans-PGE ZO-ethyI-PGE 20-methyl-PGE16-fluoro-PGE and the esters of all of those. As examples of prior artwhich disclose these E-type prostaglandin-like compounds and others ofthe E-type, see German Offenlegungschrift Nos. 1,937,675, 1,937,921,2,011,969, 2,036,471, 2,118,686, 2,121,980, 2,144,048, 2,150,361,

2,154,309, 2,165,184, 2,209,990, 2,217,044, and 2,221,443. See alsoFrench Pat. No. 2,1 19,855, Dutch Pat. application No. 7,206,316, andBelgian Pat. Nos. 779,898 and 782,822, these being available in printedform through Derwent CPI accession Nos. 76213T-B, 76383T-B, 59033T-B,and 7234OT-B, respectively.

The above-described structural variants of the E-type prostaglandins areuseful for the same purposes described above for the E-typeprostaglandins, and are used for those purposes in the ways describedabove.

For the purposes of this invention, the term prostagla'ndin-likecompounds of the E-type includes both prostaglandins of the E-type,namely PGE PGE P613 dihydro-PGE and the esters of those, and also othercarboxylic and esters thereof of the type exemplified above, namelythose which are structurally similar to the E-type prostaglandins,having a c'yclopentane moiety of formula II but with structuralvariations in either or both side chains, and causing at least part ofthe biological responses caused by E-type prostaglandins.

Also for the purposes of this invention, the term prostaglandin-likecompounds of the E-type is intended to include optically activecompounds with the same absolute configuration as optically active PGEobtained from certain mammalian tissues, for example, sheep vesicularglands or human seminal plasma. See, for example, Bergstriim et al., J.Biol. Chem. 238, 3555 (1963). This term is also intended to includeracemic compounds but not the enantiomers of said optically activecompounds. Thus, for example, the compound designated PGE means anoptically active compound with the natural configuration, and thecorresponding racemate, and the compound designated l5-methyl- PGE meansan optically active compound with the absolute configuration of F615,,and also the corresponding racemate.

Also for the purposes of this invention, the term prostaglandin-likecompounds of the E-type is intended to include not only the carboxylicacids but also the esters of said carboxylic acids. Typical esters arethose wherein the esterifying radical is alkyl of one to 12 carbonatoms, inclusive, cycloalkyl of three to 10 carbon atoms, inclusive,aralkyl of seven to 12 carbon atoms, inclusive, phenyl, and phenylsubstituted with one, 2, or 3 chloro or alkyl of one to four carbonatoms,

inclusive. Especially useful for the above described purposes are alkylesters of one to four carbon atoms, inclusive, more especially methyland ethyl esters.

One problem that has been observed in using and formulatingprostaglandin-like compounds of the E-type is the stability of thecompounds. These compounds tend to decompose, especially at roomtemperatures, e.g., about 25 C., and higher, and especially in thepresence of small amounts of acid or base. In particular, in thepresence of acid, PGE for example, changes to PGA which has the formula:

Similarly, the other prostaglandin-like compounds of the E-type changeto the corresponding compounds of the A-type or the B-type. Even inneutral solution or in the solid state, there is a gradual change ofE-types to A types and B-types.

Reasonable stability of prostaglandin-like compounds of the E-type hasbeen observed in some solutions or in solid form when those aremaintained at very low temperatures, for example, at C. or lower.However, storage under such temperature conditions is usuallyinconvenient when the compounds are being used for the above-describedpurposes.

We have now discovered that solutions of prostaglandin-like compounds ofthe PGE-type, for example, PGE in an anhydrous, water-miscible,pharmacologically-acceptable, dipolar aprotic solvent are surprisinglyand unexpectedly stable even at room temperature, e.g., about C., andabove. Stock solutions of the E-type prostaglandin-like compound soprepared, i.e., in an anhydrous, water-miscible,pharmacologically-acceptable, dipolar aprotic solvent, for example,anhydrous N,N-dimethylacetamide, can be stored at such temperatures forrelatively long periods of time, for example, up to a year or moredepending on the particular solvent and its water content,

By water-miscible is intended those solvents which mix with water in allproportions or which are so highly soluble in water that they behave asif they were completely miscible.

lt'is desirable that the solutions according to the invention berelatively concentrated, i.e., concentrated relative to the effectiveconcentration, i.e., the concentration at which the drug is used. Thuswith N,N- dimethylacetamide or dimethylsulfoxide, or like dipolaraprotic solvent, the concentration could be as high as 100 mg./ml. orso. Ordinarily it will be sufficient if the solute is present in atleast about 1 mg. per ml. Such solutions, though seemingly dilute, arerelatively quite concentrated with respect to the effectiveconcentration.

It is to be understood that pharmacologically acceptable is to be basedon the liquid or solid vehicle rather than on the stock solution. Someanhydrous solvents, for example, might not be pharmacologicallyacceptable undiluted as in the stock solution but are very much so whendiluted with a large volume of water as in enteral or parenteraladministration or when diluted into a lactose tablet or suppository basefor intravaginal or rectal administration. For example, 1 ml. of a 50without excessive decomposition. Such solutions,

I therefore, provide a satisfactory method for storing theprostaglandin-like E-type compounds. Such solutions also provide asatisfactory method for dispensing the prostaglandin-like E-typecompounds. For example, such a solution is packaged in unit dosecontainers, and when used, the contents of a container are diluted intoa liquid or' solid carrier for administration of a therapeutic dose. Forexample, the solution is dilutedinto water for enteraladministration orinto lactose tablets or a suppository base for intravaginal or rectaladministration. When parenteral administration of the prostaglandin-likeE-type compound is intended, such solutions are dispensed by sterilizingthe solution, for example, by filter sterilization, and then asepticallypackag-' ing the solution in sterile containers in unit doses, dilutingthe contents of a sterile container with a sterile miscible diluent, forexample, water, or isotonic saline or glucose solution, and thenadministering the diluted solution at a rate to administer a therapeuticdose.

While anhydrous N,N-dimethylacetamide is given by way of illustration,it is to be understood that other pharmacologically acceptable, dipolaraprotic solvents can be used. Other suitable dipolar aprotic solventsinclude tetramethylurea, hexamethylphosphoramide, dimethylsulfoxide,sulfolane, acetone and isopropyl methyl ketone. The dipolar aproticsolvents, especially N,N-dimethylacetamide, have great solvent power forprostaglandin-like E-type prostaglandins, and, moreover, give verystable solutions.

mg./ml. solution of PGE for example, diluted into 1 liter of infusionsolution gives a solution containing 0.005 percent PGE At the same timethe concentration of the solvent, 0.1 percent, is well below that safefor intravenous infusion. Thus a pharmacologically ac ceptable solventas used herein is one which on dilution into the liquid or solid vehiclecauses no untoward pharmacodynamic effect.

An anhydrous solution is to be considered as one containing not morethan 0.5 percent of water. All commercially available solvents containwater. Ordinary pure N,N-dimethylacetamide, for example, may contain upto about 0.5 percent water whereas spec trograde N,N-dimethylacetamidemay contain as little as 0.03 percent water. An anhydrous solvent,therefore, is to be considered as one containing not more than about 0.5percent water. The Karl Fischer method can be used to determine thewater content. It is actually preferred that the solvent, for example,N,N- dimethylacetamide, contain not more than about 0.1 percent water.

The invention can now be more fully understood by reference to thefollowing examples in which the parts and percentages are by weight andthe units in the C.G.S. system unless otherwise specified. Although allof these examples relate to PGE and N,N- dimethylacetamide, it is to beunderstood that other prostaglandin-like E-type compounds in both freeacid form and ester form within the above-defined scope of thisinvention, including the compounds specifically named hereinabove, aretransformed into stable solutions adapted for dispensing as set forthhereinabove, and that other anhydrous, water-miscible, pharmacologicallyacceptable, dipolar aprotic solvents than N,N- dimethylacetamide arealso used for that purpose.

EXAMPLE 1 Parenteral grade PGE is dissolved in anhydrousN,N-dimethylacetamide containing 0.4 percent water filter, e.g.,Millipore Solvinert 0.25 microns or Gelman Metricel Alpha-8, 0.2microns, aseptically packaged in 1 ml. quantities in sterile ampuls andkept under refrigeration at not more than until needed. At that time thecontents of one ampul (1 ml.) are diluted into 1 l. of infusion solutionand administered intravenously at the rate of 5 mcg. of PGE per minute.This regimen is intended for therapeutic abortion.

EXAMPLE 2 Parenteral grade PGE is dissolved in spectrogradeN,N-dimethylacetamide (0.1 percent water) in a concentration of mg. perml. The solution is filter sterilized as in Example 1 and packagedaseptically in 0.5 ml. quantities in sterile ampuls. This solution canbe stored at room temperature. It is administered in the same way andfor the same purposes as in Example 1.

EXAMPLE 3 Parenteral grade PGE is dissolved in anhydrousN,N-dimethylacetamide (0.1 percent water) in the proportions of 0.75 mg.PGE to 1.5 ml. anhydrous N,N- dimethylacetamide. The solution is thenfilter sterilized as in Example 1, aseptically packaged in 1.5 ml.quantities in sterile ampuls, and kept under refrigeration at not morethan 5 until needed. It is administered by diluting the contents of 1ampul (1.5 ml.) into 150 ml. of infusion solution and administeredintravenously at the rate of 0.5 mcg. of PGE per minute. This regimen isintended for inducing labor.

We claim:

1. A solution of a prostaglandin-like compound of the PGE-type in ananhydrous, water-miscible, pharmacologically acceptable, dipolar aproticsolvent in a concentration of at least 1 mg. per ml.

2. A solution according to claim 1 which is sterile.

3. A solution of a prostaglandin-like compound of the PGE-type inanhydrous N,N-dimethylacetamide in a concentration of at least 1 mg. perml.

4. A solution according to claim 3 which is sterile.

5. A solution according to claim 3 wherein said compound is PGE or PGEmethyl ester.

6. A solution according to claim 3 wherein said compound islS-methyl-PGE or IS-methyI-PGE, methyl ester.

7. A solution according to claim 3 wherein said compound isIS-methyl-PGE or 15-methyl-PGE methyl ester.

8. A solution according to claim 3 wherein said compound is 153-1S-methyl-PGE or 1513- l S-methyl-PGE, methyl ester.

9. A solution according to claim 3 wherein said compound is15B-l5-methyl-PGE or 15/3-15-methyl-PGE methyl ester.

10. A solution according to claim 3 wherein said compound is16,16-dimethyl-PGE or 16,16-dimethyl- PGE methyl ester.

11. A solution according to claim 3 wherein said compound is16,l6-dimethyl-PGE or 16,16-dimethyl- PGE methyl ester.

12. A solution according to claim 3 wherein said compound is l7-phenyl-l8,19,20-trinor-PGE or 17- phenyl-l 8,19,20-trinor-PGE methyl ester.

13. A solution of PGE in an anhydrous, watermiscible, pharmacologicallyacceptable, dipolar aprotic solvent in a concentration of at least 1 mg.per ml.

14. A solution according to claim 13 in which the solvent isanhydrousN,N-dimethylacetamide.

15. A solution according to claim 14 in which said N,N-dimethylacetamidecontains not more than 0.1 percent water.

16. A solution according to claim 15 which is sterile.

2. A solution according to claim 1 which is sterile.
 3. A solution of aprostaglandin-like compound of the PGE-type in anhydrousN,N-dimethylacetamide in a concentration of at least 1 mg. per ml.
 4. Asolution according to claim 3 which is sterile.
 5. A solution accordingto claim 3 wherein said compound is PGE1 or PGE1 methyl ester.
 6. Asolution according to claim 3 wherein said compound is 15-methyl-PGE1 or15-methyl-PGE1 methyl ester.
 7. A solution according to claim 3 whereinsaid compound is 15-methyl-PGE2 or 15-methyl-PGE2 methyl ester.
 8. Asolution according to claim 3 wherein said compound is 15 Beta-15-methyl-PGE1 or 15 Beta -15-methyl-PGE1 methyl ester.
 9. A solutionaccording to claim 3 wherein said compound is 15 Beta -15-methyl-PGE2 or15 Beta -15-methyl-PGE2 methyl ester.
 10. A solution according to claim3 wherein said compound is 16, 16-dimethyl-PGE1 or 16,16-dimethyl-PGE1methyl ester.
 11. A solution according to claim 3 wherein said compoundis 16, 16-dimethyl-PGE2 or 16,16-dimethyl-PGE2 methyl ester.
 12. Asolution according to claim 3 wherein said compound is17-phenyl-18,19,20-trinor-PGE2 or 17-phenyl-18,19,20-trinor-PGE2 methylester.
 13. A solution of PGE2 in an anhydrous, water-miscible,pharmacologically acceptable, dipolar aprotic solvent in a concentrationof at least 1 mg. per ml.
 14. A solution according to claim 13 in whichthe solvent is anhydrous N,N-dimethylacetamide.
 15. A solution accordingto claim 14 in which said N,N-dimethylacetamide contains not more than0.1 percent water.
 16. A solution according to claim 15 which issterile.